In major depressive disorder, there is substantial evidence that monoamines are low. Monoamines are chemicals and include, but are not limited to, the chemicals serotonin, norepinephrine and dopamine.
In major depressive episodes of major depressive disorders (MDE), there is a substantial accumulation of evidence that serotonin lowering processes exist. 5-HT stores may be low during MDE because 5-HT metabolite 5-hydroxyindoleacetic acid concentrations are often low in cerebrospinal fluid during MDE. It is thought that 5-HT release after d-fenfluramine administration is reduced during MDE because the prolactin release after d- and (d,l)-fenfluramine is often reduced during MDE. A role for 5-HT in mood modulation has also been proposed, because mood lowering after tryptophan depletion is often observed in subjects with either a family history of depressive episodes or a past history of depressive episodes.
Upregulation of post synaptic 5-HT2 receptors in suicide victims may also suggest that neuronal 5-HT release is low during MDE. The majority of suicide victims have a diagnosis of MDE and some of the post-mortem investigations of 5-HT2 receptors in suicide victims exclusively sampled depressed suicide victims. 5-HT2 receptor density regulates in response to 5-HT changes when MAO-A is inhibited or when tryptophan hydroxylase is inhibited such that decreases in 5-HT are associated with increased 5-HT2 density and increases in 5-HT are associated with decreases in 5-HT2 density.
There is a paucity of imaging studies of 5-HT2 receptors in drug free MDE. Most such studies recruit subjects who were recently withdrawn from medication. Meyer et al. recently published an article in the American Journal of Psychiatry which found increased 5-HT2 BP in MDE with negativistic, pessismistic dysfunctional attitudes.
Although there have been fewer investigations of norepinephrine and dopamine abnormalities during MDE, a number of reports suggest that there could be norepinephrine and dopamine lowering process during MDE as well. Several adrenergic receptor abnormalites found during MDE can occur during norepinephrine lowering processes. These include a significant proportion of investigations reporting increased β2 receptor (post-synaptic) density in suicide victims, increased α2 adrenergic receptor density in depressed suicide victims and decreased (presynaptic) norepinephrine transporter density in locus coeruleus. α2 Receptors and β2 receptors increase in density under some norepinephrine depleting paradigms. The presynaptic norepinephrine transporter decreases in density when norepinephrine is chronically low. While suicide victims may have a variety of psychiatric diagnoses, the most common is MDE. These findings provide support for a norepinephrine lowering process during MDE.
Indirect investigations of dopamine during MDE suggest that dopamine may be low, especially when motor retardation is present. Increased D2 binding potential (post-synaptic receptor) may occur when extracellular dopamine is low. We currently have an article in press in the American Journal of Psychiatry which found greater D2 BP during MDE with motor retardation [1]. Subjects were medication free for 6 months or more and were non-smoking. There are also some reports of increased D2 BP during MDE in other samples that have not selected medication free subjects. We previously found decreased striatal DAT BP in drug free, non-smoking subjects with MDE [2]. Neumeister et al. found decreased striatal DAT BP in medication subjects with seasonal affective disorder and Klimek et al. report decreased DAT density in amygdala. The DAT, a presynaptic receptor, is reduced after chronic dopamine depletion, thus a reduced striatal DAT BP during MDE is also consistent with a dopamine depleting process during MDE. Decreased cerebrospinal fluid levels of dopamine metabolite homovanillic acid is often reported during MDE with motor retardation. This is also suggestive of low brain dopamine during MDE with motor retardation.
Monoamine oxidase A (MAO-A) is an enzyme found throughout the body. In the brain, a predominant location for this enzyme is on the outer mitochondria membranes in neurons [11]. In the human central nervous system, monoamine oxidase A density is highest in brainstem (locus coeruleus), lower in the hippocampus, cortex, striatum, and minimal in white matter tissue [11].
Serotonin is a high affinity substrate for MAO-A [12, 13]. MAO-A is detectable in serotonin releasing neurons [14]. MAO-A clearly influences extracellular serotonin because administration of MAO-A inhibitors increase extracellular serotonin from 20 to 200 percent, depending upon drug, dose and region [15-17]. This has been found in at least seven separate studies and across five different MAO-A inhibitors (clorgyline, moclobemide, brofaromine, harman, befloxatone) [15-17] and the finding was present in a variety of brain regions including prefrontal cortex, hippocampus, and superior raphe nuclei. In these paradigms it is often demonstrated that brain 5-HIAA is reduced [15]. There is some question as to whether brofaromine is selective, but to our knowledge the other MAO-A inhibitors are considered selective. Extracellular serotonin is also raised substantively (100-200%) in prefrontal cortex, hippocampus and superior raphe nuclei in the knockout model of MAO-A [80].
The effect of MAO-B inhibitors upon extracellular 5-HT, is reported to be more modest than MAO-A inhibitors. After MAO-B inhibition, 5-HT was raised from 0% (non-significant) to 20% [16, 17]. MAO-B inhibitors had the least effect in cortex and greatest (albeit moderate) effect in the raphe nuclei [16, 17].
Norepinephrine is a high affinity substrate for MAO-A. MAO-A is easily detectable in cells that synthesize norepinephrine [11, 14. 19]. Under conditions of MAO-A inhibition, extracellular norepinephrine is increased in prefrontal cortex as well as hippocampus [20, 21] which argues that MAO-A has a substantial role in controlling extracellular norepinephrine in these brain regions. Extracellular norepinephrine is elevated in prefrontal cortex and hippocampus in MAO-A knockout mice [22].
Dopamine is a high affinity substrate for MAO-A [13]. Administration of MAO-A inhibitors increases extracellular dopamine in striatum under baseline conditions as well as during precursor loading paradigms [23, 24]. We are aware of a couple of reports detecting MAO-A in dopamine synthesizing neurons [25], although it has been postulated that MAO-A outside of dopamine synthesizing neurons is more likely to account for the elevations in extracellular striatal dopamine after MAO-A inhibition [11].
The vast majority of longstanding antidepressant medication treatments for major depressive episodes raise monoamines. Most antidepressant medications raise monoamines by inhibiting the reuptake of serotonin, norepinephrine or dopamine. Some antidepressant medications raise monoamines by inhibiting the activity of monoamine oxidase A and/or monoamine oxidase B.
It has been repeatedly demonstrated that medications that raise monoamines such as serotonin reuptake inhibitors, norepinephrine reuptake inhibitors, dopamine reuptake inhibitors and monoamine oxidase inhibitors all can reduce the risk of recurrence of a depressive episode [26]. Since these medications raise monoamines, it follows that there is a relationship between chronic monoamine levels and propensity for recurrence of depressive episodes.
In people with a history of depressive episodes, acute reductions in monoamines are known to temporarily result in recurrence of low mood. The tryptophan depletion paradigm is a comparison of two oral amino acid dosings. One dosing (part A) is the administration of an amino acid mixture that is high in large amino acids yet devoid of tryptophan. The other dosing (part B—control) contains the same amino acid mixture with tryptophan added. They are given in a randomized double blind fashion. By giving a relative deficiency in tryptophan in part A, one obtains a decrease in the transport of tryptophan into the brain. Since tryptophan is the precursor to 5-HT, and since 5-HT itself cannot cross the blood brain barrier, this results in lower brain 5-HT. Changes in mood observed after part A in comparison to part B are attributed to a lower level of 5-HT. The tryptophan depletion paradigm, is associated with recurrence of lower mood, especially in people who have a history of depressive episodes and are in recovery. This has been observed in both medication treated and medication free subjects with a history of major depressive episodes.
Alphamethylparatyrosine (AMPT) is an inhibitor of tyrosine hydroxylase and administration of this medication lowers extracellular norepinephrine (in multiple brain regions) and striatal dopamine. When AMPT given to subjects with a history of depressive episodes, recurrence of sustained low mood is common.